Functional Significance of Ryanodine Receptor-Mediated Calcium Leaks in Sarcoplasmic Reticulum Membranes

Summary

Since their original purification and identification as the main Ca²⁺ efflux pathway from sarcoplasmic reticulum (SR) membranes, ryanodine receptors (RyRs) have attracted an enormous level of research interest. This is not surprising for several reasons. First, they sit at the epicentre of regulatory mechanisms involved in excitation-contraction coupling. Second, RyRs represent the main building blocks of a huge multimeric protein assembly with a molecular mass estimated to be around 2.3 mega Daltons. Third, RyRs are able to bind an unprecedented number of regulatory proteins, toxins and other molecules producing, in many cases, quite complex effects upon its Ca²⁺ ion channel properties. Much remains to be determined about how in vitro kinetic and features of RyR activation and inactivation account for observed Ca²⁺ release properties in vivo. Some studies favor the idea that in intact SR membranes ATP-dependent Ca²⁺ pumps (SERCA) can also influence both activation and inactivation of Ca²⁺ release. More recently, however, we have come to appreciate the significant leakiness of SR membranes to Ca²⁺ at rest and the possibility that this occurs primarily through activation of RyRs. A number of more recent lines of evidence suggest this leakiness has some physiological significance in activating RyRs to initiate Ca2 + sparks and trigger Ca²⁺ release. Because of the potential importance of this to RyR function a great deal of interest has been generated in an attempt to reveal underlying regulatory mechanism of RyR leakiness. A class of immunophillin binding proteins, known as FKBP12/12.6, is now thought to play a very important role in determining RyR leaks in both normal and pathological settings. However, species and tissue differences in FKBP12/12.6 distribution make it hard to make any firm generalizations, at this point, regarding in vivo RyR leak regulation.